Observation of the effect of gravity on the motion of antimatter.

Einstein's general theory of relativity from 19151 remains the most successful description of gravitation. From the 1919 solar eclipse2 to the observation of gravitational waves3, the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory4 appeared in 1928; the positron was observed5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter7-10. In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP.

Laser cooling of antihydrogen atoms.

The photon-the quantum excitation of the electromagnetic field-is massless but carries momentum. A photon can therefore exert a force on an object upon collision1. Slowing the translational motion of atoms and ions by application of such a force2,3, known as laser cooling, was first demonstrated 40 years ago4,5. It revolutionized atomic physics over the following decades6-8, and it is now a workhorse in many fields, including studies on quantum degenerate gases, quantum information, atomic clocks and tests of fundamental physics. However, this technique has not yet been applied to antimatter. Here we demonstrate laser cooling of antihydrogen9, the antimatter atom consisting of an antiproton and a positron. By exciting the 1S-2P transition in antihydrogen with pulsed, narrow-linewidth, Lyman-α laser radiation10,11, we Doppler-cool a sample of magnetically trapped antihydrogen. Although we apply laser cooling in only one dimension, the trap couples the longitudinal and transverse motions of the anti-atoms, leading to cooling in all three dimensions. We observe a reduction in the median transverse energy by more than an order of magnitude-with a substantial fraction of the anti-atoms attaining submicroelectronvolt transverse kinetic energies. We also report the observation of the laser-driven 1S-2S transition in samples of laser-cooled antihydrogen atoms. The observed spectral line is approximately four times narrower than that obtained without laser cooling. The demonstration of laser cooling and its immediate application has far-reaching implications for antimatter studies. A more localized, denser and colder sample of antihydrogen will drastically improve spectroscopic11-13 and gravitational14 studies of antihydrogen in ongoing experiments. Furthermore, the demonstrated ability to manipulate the motion of antimatter atoms by laser light will potentially provide ground-breaking opportunities for future experiments, such as anti-atomic fountains, anti-atom interferometry and the creation of antimatter molecules.

Achieving ultra-low and -uniform residual magnetic fields in a very large magnetically shielded room for fundamental physics experiments.

High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of ∼1.4m3, the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from 12h down to 1.5h.

A large 'Active Magnetic Shield' for a high-precision experiment: nEDM collaboration.

We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about 105 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to ±50µT (homogeneous components) and ±5µT/m (first-order gradients), suppressing them to a few µT in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

Sympathetic cooling of positrons to cryogenic temperatures for antihydrogen production.

The positron, the antiparticle of the electron, predicted by Dirac in 1931 and discovered by Anderson in 1933, plays a key role in many scientific and everyday endeavours. Notably, the positron is a constituent of antihydrogen, the only long-lived neutral antimatter bound state that can currently be synthesized at low energy, presenting a prominent system for testing fundamental symmetries with high precision. Here, we report on the use of laser cooled Be+ ions to sympathetically cool a large and dense plasma of positrons to directly measured temperatures below 7 K in a Penning trap for antihydrogen synthesis. This will likely herald a significant increase in the amount of antihydrogen available for experimentation, thus facilitating further improvements in studies of fundamental symmetries.

TBX2 interacts with heterochromatin protein 1 to recruit a novel repression complex to EGR1-targeted promoters to drive the proliferation of breast cancer cells.

Early Growth Response 1 (EGR1) is a stress response transcription factor with multiple tumour suppressor roles in breast tissue, whose expression is often lost in breast cancers. We have previously shown that the breast cancer oncogene TBX2 (T-BOX2) interacts with EGR1 to co-repress EGR1-target genes including the breast tumour suppressor NDRG1. Here, we show the mechanistic basis of this TBX2 repression complex. We show that siRNA knockdown of TBX2, EGR1, Heterochromatin Protein 1 (HP1) isoforms and the generic HP1-associated corepressor protein KAP1 all resulted in growth inhibition of TBX2-expressing breast cancer cells. We show that TBX2 interacts with HP1 through a conserved HP1-binding motif in its N-terminus, which in turn leads to the recruitment of KAP1 and other associated proteins. Mutation of the TBX2 HP1 binding domain abrogates the TBX2-HP1 interaction and loss of repression of target genes such as NDRG1. Chromatin-immunoprecipitation (ChIP) assays showed that TBX2 establishes a repressive chromatin mark, specifically H3K9me3, around the NDRG1 proximal promoter coincident with the recruitment of the DNA methyltransferase DNMT3B and histone methyltransferase (HMT) complex components (G9A, Enhancer of Zeste 2 (EZH2) and Suppressor of Zeste 12 (SUZ12)). Knockdown of G9A, EZH2 or SUZ12 resulted in upregulation of TBX2/EGR1 co-regulated targets accompanied by a dramatic inhibition of cell proliferation. We show that a generic inhibitor of HMT activity, DzNep, phenocopies expression of an inducible dominant negative TBX2. Knockdown of TBX2, KAP1 or HP1 inhibited NDRG1 promoter decoration specifically with the H3K9me3 repression mark. Correspondingly, treatment with a G9A inhibitor effectively reversed TBX2 repression of NDRG1 and synergistically downregulated cell proliferation following TBX2 functional inhibition. These data demonstrate that TBX2 promotes suppression of normal growth control mechanisms through recruitment of a large repression complex to EGR1-responsive promoters leading to the uncontrolled proliferation of breast cancer cells.

The role of BRCA1 in transcriptional regulation and cell cycle control.

The exact functions of BRCA1 have not been fully described but it now seems apparent that it has roles in DNA damage repair, transcriptional regulation, cell cycle control and most recently in ubiquitylation. These functions of BRCA1 are most likely interdependent but this review will focus on the role of BRCA1 in relation to transcriptional regulation and in particular how this impacts upon cell cycle control. We will (i) describe the structure of BRCA1 and how it may contribute to its transcription function; (ii) describe the interaction of BRCA1 with the core transcriptional machinery (RNA polII); (iii) describe how BRCA1 may regulate transcription at an epigenetic level through chromatin modification; (iv) discuss the role of BRCA1 in modulating transcription through its association with sequence-specific transcription factors. Finally, we will discuss the possible effects of BRCA1 transcriptional regulation on downstream targets with known roles in cell cycle control.

BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.

Mutation of a putative ADP-ribosylation motif in the Pasteurella multocida toxin does not affect mitogenic activity.

Pasteurella multocida toxin (PMT) is a potent mitogen for Swiss 3T3 fibroblasts and cytotoxic to embryonic bovine lung cells. Site-directed mutagenesis was used to investigate the functional significance of a three amino acid motif in PMT that is present in five other bacterial protein toxins which exhibit ADP-ribosyl transferase activity. Crude lysates of mutant clones were fully cytotoxic for embryonic bovine lung cells. Purified mutant toxin was also as effective at stimulating inositol phosphate turnover and nucleic acid synthesis as wild type toxin. We conclude that this motif has no functional significance in Pasteurella multocida toxin.

Diagnosis of attention-deficit/hyperactivity disorder and use of psychotropic medication in very young children.

CONTEXT: Increases in diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) have elicited public and professional concern. Research suggests that this trend warrants the inclusion of previously underdiagnosed children and adults. It is not clear whether this trend includes young children. OBJECTIVE: To identify patterns of diagnosis and treatment of ADHD in very young children over time. DESIGN: Descriptive study of Michigan Medicaid claims data. PATIENTS: Inclusion criteria included recorded ADHD diagnosis, continuous Medicaid eligibility during a 15-month period, and age 3 years or younger at the first date of service. MAIN OUTCOME MEASURES: Diagnoses of ADHD, conditions commonly comorbid with ADHD, other chronic health conditions, and injuries; treatments such as psychological services and psychotropic medication; and the number of ambulatory visits. RESULTS: We identified 223 children aged 3 years or younger diagnosed with ADHD. Many had conditions commonly comorbid with ADHD (44%), other chronic health conditions (41%), and injuries (40%). More than half received psychotropic medication (57%); fewer received psychological services (27%). Twenty-two different psychotropic medications were used. Patterns included more than 1 psychotropic medication (46%) in 30 combinations of simultaneous use and 44 combinations of sequential use. The mean number of ambulatory visits was 18. CONCLUSIONS: Children aged 3 years or younger had ADHD diagnosed and received markedly variable psychotropic medication regimens. Little information is available to guide these practices. The presence of comorbid conditions and injuries attests to these children's vulnerability. Resources must be identified that will enable physicians to better respond to the compelling needs of these children and their families.

Use of skin-cancer prevention strategies among farmers and their spouses.

Epidemiologic studies show that farmers are at increased risk of skin cancer, presumed to be secondary to the increased time they spend outdoors with exposure to the sun. We surveyed a random sample of farmers and their spouses 40 years of age or older from four rural counties in Michigan on their knowledge, attitudes, and behavior regarding protection of their skin from the sun and screening medical exams for skin cancer. Questionnaires were completed by 1,342 farmers and their spouses. This was a response rate of 63.5%. Eighty to ninety percent knew the changes in the skin that could indicate cancer and required medical follow-up. Only 40% of the men and 65% of the women were likely to protect their skin when they went outdoors. Increasing age and personal history of skin cancer increased the likelihood of both men and women protecting their skin when they went outside. Additionally, higher-income women were likely to use sun protection. Despite the fact that 90% of the respondents had had a physical examination in the last three years, less than one third reported ever having had their skin examined for cancer. Increasing age, income, and education increased the likelihood of having had such an exam. The majority of those who had had a skin exam had the exam for a particular skin problem, and not as part of a routine physical examination. Farmers and their spouses need to increase their use of sun protection when going outside. Additionally, health care providers need to routinely include examination of the skin for skin cancer and alert their patients that it is being performed.

Assessing medical and dental students' knowledge of preventive medicine.

This cross-sectional study examined medical and dental students' knowledge of preventive medicine. The purpose of the study was to assess the knowledge of preventive medicine--both epidemiological and clinical--that students demonstrate as they enter medical and dental school and acquire during training. The results of a two-group (medical versus dental school) by three-time (first-, second-, and third-year level) analysis of variance of students' mean examination scores showed significant main effects for school (F = 28.3, P less than .001) and training level (F = 24.5, P less than .001), and a significant school-by-training level interaction (F = 13.9, P less than .001). Medical students at higher training levels demonstrated greater knowledge of preventive medicine. In contrast, there were no significant differences by year of training among the dental students on the total test or on the epidemiological or clinical subscales. Both the dental and medical students demonstrated greater knowledge of clinical applications than of epidemiological foundations (t = 4.21, P less than .01). Dental students performed better than medical students on items that focused on diseases and risk factors that manifest symptoms more likely to be observed in dentistry than in general medical practice. The findings underscore the need to demonstrate practice relevance when teaching preventive medicine.

Exploratory factor analysis of students' ratings of a problem-based learning curriculum.

PURPOSE: To identify the factor structure underlying medical students' initial experience with a problem-based learning (PBL) curriculum and to examine the stability of this structure as students acquire further experience with PBL. METHOD: The PBL curriculum at the Michigan State University College of Human Medicine begins in the students' second year and is divided into 11 domains. In 1992-93 students were asked to evaluate their learning experiences in the first and last domains of their first PBL semester, by using a five-point Likert scale to rate 19 items. Principal-components analysis and varimax rotation were used to identify the factors underlying the students' ratings. RESULTS: Ratings of the first and last domains were available from 101 and 71 students, respectively. Analysis yielded four meaningful factors: learning materials, small-group process, tutor effectiveness, and academic support. These four factors shifted in relative importance as the students progressed through the curriculum: for the first domain, tutor effectiveness accounted for the highest percentage of variance in the data; for the last domain, this factor ranked third, after learning materials and small group process. Internal reliabilities for the ratings of the last domain of the semester were higher and more consistent, ranging from .92 to .97. CONCLUSION: The students' initial dependence on the tutor progressed to an emphasis on learning resources. This shift is congruent with the theoretical model of the dynamics of PBL. The results suggest that the survey instrument provides a reliable measure of the multidimensional constructs underlying students' experience with PBL.

Faculty expectations and primary care residents' perceptions concerning residents' growth in competence at one medical school.

The authors studied at one school both the developing confidence of primary care residents and the expectations of both internal medicine and specialty faculty members regarding the abilities of the residents. From 1980 to 1988, residents in the study institution's program in internal medicine primary care completed self-assessments concerning their diagnostic and management skills in primary care and several specialties at the start of their training and at the ends of their first, second, and third years. In 1988, the authors elicited the expectations of the primary care and specialty faculties regarding the levels of competence that residents should achieve in the specialties by the end of their third year. When the faculty assessments were compared, the specialists were found to ascribe greater levels of autonomy to residents. The authors conclude that involving residents and faculty members from various disciplines in developing expectations and evaluation criteria can enhance faculty members' perceptions of residents' clinical competence and residents' achievement of it.

Sensitivity to patients' psychosocial concerns: relationships among ratings by primary care and traditional internal medicine house officers and patient self-assessments.

This study examined house officers' sensitivity to patients' psychosocial concerns. Primary care house officers, traditionally trained internal medicine house officers, a social worker, and 104 ambulatory care patients independently completed an assessment instrument to indicate the extent to which a set of 20 defined psychosocial issues concerned the patients. We examined the magnitude of difference and extent of correlation in the independent reports of the patient, house officer, and social worker. These analyses were conducted on both the individual psychosocial issues and on sets of concerns derived from an oblique rotation factor analysis of the patients' responses. Primary care trainees' assessments of their patients' concerns correlated more frequently with the independent assessments of the patients and a social worker than did the judgments of the traditionally trained house officers. The factor analysis identified six factors that accounted for 64.4% of the variance in patients' responses. The correlations between the primary care trainees' and patients' assessments were statistically significant on five of these six factors; the correlations between the traditionally trained residents' and patients' assessments were statistically significant on two of the factors. These results provide evidence of the primary care house officer training program's achievement of the goal of enhanced physician awareness of patients' psychosocial concerns. The results also support training efforts aimed at increasing physicians' ability to assess their patients' psychosocial concerns.

Skin cancer prevention and detection practices in a Michigan farm population following an educational intervention.

Farmers face an increased risk of skin cancer, presumed to be secondary to their increased occupational exposure to sunlight. This study examines skin cancer prevention and detection beliefs and practices among adult farmers in defined control and comparison farming communities in four contiguous counties of Michigan, before and after a community-based educational intervention. The educational intervention included mailing packets containing information on skin cancer risks and community sources for screening, disseminating articles in local newspapers on skin cancer prevention and control measures, and providing information and screening at local county fairs and agricultural community fairs. The responses of 2,999 survey participants were analyzed to identify the interrelationships among their beliefs and their descriptions of their (primary preventive) self-care and professional medical care seeking (for detection and treatment) practices. Factors associated with the likelihood of skin cancer screening and with measures of knowledge and practices associated with medical care of skin cancer were examined. The intervention appeared to improve the practice of preventive behaviors and seeking medical care.

Activities of potential tumour marker enzymes during induced differentiation in HL-60 and U-937 cells.

HL-60 and U-937 cells were used as models to assess the involvement of the enzymes of thymidine metabolism in differentiation. Both cell types showed decreased thymidine kinase and thymidylate synthase but increased thymidine phosphorylase activities in response to the induction of differentiation by dimethylsulfoxide and 12-O-tetradecanoylphorbol 13-acetate. This was accompanied by a greater than three-fold increase in the stimulation of superoxide production in both cell lines. Thymidylate synthase and thymidine kinase activities were noted as potential markers of leukaemic cell proliferation while thymidine phosphorylase and superoxide production correlated well with differentiated phenotypes. Prolonged treatment of U-937 by 12-O-tetradecanoylphorbol 13-acetate resulted in a marked de-differentiation, indicating overstimulation of one or more of the isoforms of protein kinase C.

S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability.

Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.

Diagnosis of paediatric tuberculosis using sputum induction in Botswana: programme description and findings.

SETTING: Four public hospitals in Botswana, a high tuberculosis (TB) burden setting. OBJECTIVES: To assess the feasibility and utility of sputum induction in the diagnosis of paediatric TB. DESIGN: From 2008 to 2010, children aged ≤18 years referred for suspected pulmonary TB underwent sputum induction. Confirmed TB was defined as the presence of at least one of the signs and symptoms suggestive of TB and positive Mycobacterium tuberculosis culture. Information on TB-associated symptoms (cough, fatigue, night sweats, low appetite, chest pain, weight loss, haemoptysis and contact with a TB case) was collected for three risk groups: human immunodeficiency virus (HIV) positive children, HIV-negative children aged <3 years and HIV-negative children aged ≥3 years. RESULTS: The median age of the 1394 subjects who underwent sputum induction was 3.8 years (IQR 1.3-8.4); 373 (27%) were HIV-positive, 419 (30%) were HIV-negative and 602 (43%) had unknown HIV status. TB was confirmed in 84 (6.0%); cases were more likely to have weight loss, chest pain or TB household contacts. There were no serious complications attributable to sputum induction during and after the procedure; only 0.8% (9/1174) of patients reported minor complications. CONCLUSIONS: In Botswana, paediatric sputum induction was feasible, safe and assisted bacteriological confirmation in a subgroup of children treated for TB.